The long-term objective of this proposal is to identify intrinsic negative modulators of inflammation-induced fibrosis, an incurable complication of Crohn's disease. The key to controlling fibrosis is to define mechanisms which permit normal wound healing but prevent these healing responses from becoming excessive. Considerable evidence indicates that locally expressed insulin-like growth factor-I (IGF-I) is upregulated in myofibroblasts at sites of fibrosis in Crohn's disease and in animals models with experimentally induced intestinal inflammation. Preliminary evidence supports the hypothesis that suppressor of cytokine signaling-2 (SOCS2) limits the fibrogenic effects of IGF-I in the inflamed intestine. After acute colitis, mice deficient in both SOCS2 alleles show increased collagen deposition and augmented IGF-I expression compared to wild type (WT) mice suggesting that SOCS2 may suppress inflammation-induced fibrosis mediated by IGF-I. One aim of this study is to determine the mechanism by which SOCS2 limits IGF-I action. These studies will use cultured myofibroblasts which overexpress SOCS2 to define those signaling molecules within the IGF-I pathway that are inhibited by SOCS2. The second aim is to test the hypothesis that mice with mesenchymal cell-specific ablation of SOCS2 show more severe fibrosis than WT littermates after acute mucosal injury induced by sodium dextran sulfate (DSS) or colitis induced by trinitrobenzene sulfonic acid (TNBS). Defining how SOCS2 limits fibrosis may provide new insights into strategies or therapies that limit or prevent fibrosis in Crohn's disease.